M. Manning et al., Nature, 308 652 (1984) and U.S. Pat. No. 4,469,679 have disclosed that the terminal glycine unit at the 9-position of certain vasopressin-like antagonists can be removed or replaced by L or D-Ala, Ser or Arg without necessarily affecting binding at vasopressin receptors.
U.S. Pat. Nos. 4,481,194 and 4,481,193 discloses that either removing proline at position 7 or both proline and glycine at positions 7 and 9 from the structures of vasopressin antagonists gives compounds which retain substantial, but somewhat reduced, antagonist activity.
The vasopressin-like compounds of this invention have structures which are distinguished over the prior art in that two basic amino acid units, such a arginine or lysine, are attached directly to the disulfide VSP ring. The compounds are very potent vasopressin antagonists.
In the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. In certain structural formulas, the thio members of the Cap, Mpa and Cys units are added for clarity.
Certain of the peptide art designations used herein are the following: Cap, .beta.-mercapto-.beta.,.beta.-cycloalkylenepropionic acid; Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Mpr, .beta.-mercaptopropionic acid; dPen, .beta.-mercapto-.beta.,.beta.-dimethylpropionic acid or desaminopenicillamine; Tyr (Alk), O-alkyltyrosine; Abu, .alpha.-amino-n-butyric acid; Chg, cyclohexylglycine; Cha, cyclohexylalanine; Pba, .alpha.-aminophenylbutyric acid; Gln, glutamic acid amide or glutamine; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Phe (4'-Alk), 4'-alkylphenylalanine; MeAla, N-methylalanine; Val, valine; Ile, isoleucine; Nle, norleucine; Leu, leucine; Ala, alanine; Lys, lysine; Arg, arginine; HArg, homoarginine; MeArg, N-methylarginine; MeHArg, N-methylhomoarginine; MeLys, N-methyllysine; Met, methionine; Asn, asparagine; Sar, sarcosine; Tos, tosylate; BHA, benzhydrylamine; DMAP, 4-dimethylaminopyridine; DIEA, diisopropylethylamine; HF, hydrogen fluoride; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; Boc, t-butyloxycarbonyl; Z, benzyloxycarbonyl; VSP, vasopressin; HBT, hydroxybenzotriazole; ACM, acetamidomethyl; Mpa, noncyclic .beta.-mercaptopropionic acids. In the definitions such as MeArg above, Me denotes a methyl located on the amido nitrogen of the peptide unit concerned.
"Alk" represents a lower alkyl of 1-4 carbons. For example, these may be optionally attached to the oxygen substituent of a tyrosine unit at position 2, to the N-terminal nitrogen of the tail, or to the 4'-position of a Phe unit at position 3. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. Ethyl is preferred. When the term, "vasopressin", is used, it means L-arginine vasopressin (AVP) unless otherwise modified. The 1-(.beta.-mercaptocycloalkylene)propionic acid unit (Cap) at position 1 is often referred herein as Pmp for convenience since the pentamethylene containing unit is preferred. All the .beta.-mercaptopropionic acids may be, at times, referred to herein as Mpr.